. The application proposes to continue to explore, using a prospective study design, the associations of specific biochemical factors with subsequent development and diagnosis of prostate cancer. Blood samples to be used in this study were collected at baseline in 1982 from 14,916 men in the ongoing Physicians Health Study. The blood will be analyzed, using a matched, nested, case-control design to evaluate hypotheses in three main areas: markers for early detection, hormonal factors, and nutritional biochemical factors. For early detection, the application posits that determination of plasma percent free PSA will markedly improve the sensitivity and specificity of PSA, especially for those with PSA values near the conventional level of "positive" (4.0 ng/ml). The plan is to assess the value of prostate-specific membrane antigen (PSMA) for early detection of metastatic disease. There are also plans to assay hormone levels (testosterone, dihydrotestosterone, 3a-androstanediol glucuronide, SHBG, estradiol) in plasma to relate these to prostate cancer risk. Analysis of the impact of genetic variations in the genes coding for the androgen receptor and 5-alpha-reductase (an important enzyme in androgen metabolism) will add further knowledge about prostate cancer aetiology, and will permit assessment of interactions with hormone levels. The major nutritional hypotheses relate to possible protective effects of lycopene and vitamin E, and possible adverse effects of specific fatty acids (especially alpha-linolenic acid and trans-fatty acids). In addition, studies are planned to explore interactions between the baseline carotenoid levels and the beta-carotene intervention. Prostate cancer endpoints are routinely documented as part of the trial follow-up, which is funded from other sources. The blood samples are already available for analysis. Hence, the proposed analysis will make efficient use of existing resources which provide the basis for a prospective study of prostate cancer. About 1,234 cases are projected by the end of the grant period, yielding sufficient statistical power for informative results.